Hydroxyformamidine derivatives and medicines containing the same

ABSTRACT

Pharmaceutical agents for inhibiting the production of 20-HETE which participates in constriction or dilation of microvessels in major organs such as the kidneys and the cerebral blood vessels, or participates in causing cell proliferation are provided. The present invention relates to hydroxyamidine compounds represented by the formula:                    
     wherein R 1  represents a group represented by the formula: R 2 —(CH 2 ) m — (wherein R 2  represents a C 3-8  cycloalkyl group, a C 2-6  alkoxycarbonyl group, a C 2-10  alkenyl group, a C 2-6  alkynyl group, a substituted or non-substituted aryl group, or the like, and m is an integer of 1 to 8), a group represented by the formula: R 3 —A— (wherein R 3  represents a hydrogen atom, a C 1-6  alkoxy group, a C 3-8  cycloalkoxy group, or the like, and A represents a straight-chain C 2-10  alkylene group which may be substituted with a C 1-6  alkyl group or a trifluoromethyl group), or a C 3-8  cycloalkyl group, and X represents an oxygen atom or a sulfur atom, 
     or pharmaceutically acceptable salts thereof, and relates to medicines including the same as active ingredients.

TECHNICAL FIELD

The present invention relates to hydroxyformamidinopyridine derivatives inhibiting a synthase of 20-hydroxyeicosatetraenoic acid (20-HETE) biosynthesized from arachidonic acid.

BACKGROUND ART

Prostaglandins produced by cyclooxygenase and leucotrienes produced by lipoxygenase have been well known as physiologically active substances synthesized from arachidonic acid. Recently, it has been elucidated that 20-HETE, which is produced from arachidonic acid by the cytochrome P450 family enzymes, functions in various manner in vivo (J. Vascular Research, vol. 32, p. 79 (1995)). It has been reported that 20-HETE induces constriction or dilation of microvessels in major organs such as the kidneys and the cerebral blood vessels, and causes cell proliferation, and it is suggested that 20-HETE plays important physiological roles in vivo, and participates in various kidney diseases, cerebrovascular diseases, and circulatory diseases (J. Vascular Research, vol. 32, p. 79 (1995); Am. J. Physiol., vol. 277, p. R607 (1999); and the like).

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a pharmaceutical agent for inhibiting the production of 20-HETE which participates in constriction or dilation of microvessels in major organs such as the kidneys and the cerebral blood vessels, or participates in causing cell proliferation.

As a result of various studies in order to solve the above problem, the present inventors have discovered that aromatic compounds having a specific substructure, and in particular, hydroxyformamidine compounds as pyridine derivatives, unexpectedly possess the inhibitory activity for 20-HETE synthase, to accomplish the present invention.

That is, the present invention relates to a hydroxyformamidine compound represented by the general formula (I) as follows:

wherein R¹ is a group represented by the formula: R²—(CH₂)_(m)— (wherein R² is a C₃₋₈ cycloalkyl group, a C₂₋₆ alkoxycarbonyl group, a C₂₋₁₀ alkenyl group, a C₂₋₆ alkynyl group, a substituted or non-substituted aryl group, a furyl group, an oxolanyl group, a substituted or non-substituted dioxolanyl group, an oxanyl group, a substituted or non-substituted dioxanyl group, a benzodioxanyl group, a piperidyl group, an N—(C₁₋₆ alkyl)piperidyl group, a substituted or non-substituted pyridyl group, a thienyl group, a substituted or non-substituted thiazolyl group, or a bicyclo[2.2.1]heptanyl group, and m is an integer of 1 to 8), a group represented by the formula: R³—A— (wherein R³ is a hydrogen atom, a C₁₋₆ alkoxy group, a C₃₋₈ cycloalkoxy group, a di(C₁₋₆ alkyl)amino group, a substituted or non-substituted arylamino group, a C₁₋₆ alkyl (substituted or non-substituted aryl)amino group, a C₁₋₆ alkylthio group, a C₁₋₆ alkoxy C₁₋₆ alkoxy group, a di(C₁₋₆ alkyl)amino C₁₋₆ alkoxy group, a hydroxy group, an acetoxy group, an arylthio group, an aryloxy group, a phthalimidoyl group, a piperidino group, a pyridylthio group, a pyrrolidinyl group, a pyrrolyl group, a morpholino group, or a substituted or non-substituted 2,6-purindion-7-yl group, and A is a straight-chain C₂₋₁₀ alkylene group which may be substituted with a C₁₋₆ alkyl group or a trifluoromethyl group), or a C₃₋₈ cycloalkyl group, and X is an oxygen atom or a sulfur atom,

or a pharmaceutically acceptable salt thereof.

In the compounds of the general formula (I) described above, it is preferable that X is an oxygen atom. In addition, it is more preferable that X is an oxygen atom and R¹ is a group represented by the formula: R⁴—B— (wherein R⁴ is a di(C₁₋₆ alkyl)amino group, a di(C₁₋₆ alkyl)amino C₁₋₆ alkoxy group, a piperidino group, a pyrrolidinyl group, or a morpholino group, and B is a straight-chain C₂₋₆ alkylene group which may be substituted with one or two methyl groups).

The hydroxyformamidine compounds or pharmaceutically acceptable salts thereof described above are employed in a medicament comprising them as active ingredients. Preferably, they are employed as an inhibitor for production of 20-hydroxyeicosatetraenoic acid (20 HETE), or are employed as a therapeutic agent for kidney diseases, cerebrovascular diseases, or circulatory diseases.

The terms used in the present invention are defined in the following. In the present invention, “C_(x-y)” means that the group following the “C_(x-y)” has a number of carbon atoms x-y.

The C₁₋₆ alkyl group means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms. A C₁₋₄ alkyl group is preferable. As examples of C₁₋₆ alkyl groups, mention may be made of, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, and the like.

The C₁₋₆ alkoxy group means a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms. A C₁₋₄ alkoxy group is preferable. As examples of C₁₋₆ alkoxy groups, mention may be made of, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, and the like.

The C₁₋₆ alkylthio group has a combined structure of a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms and one thio group (—S—). A C₁₋₄ alkylthio group is preferable. As examples of C₁₋₆ alkylthio groups, mention may be made of, for example, a methylthio group, an ethylthio group, a propylthio group, and the like.

The C₃₋₈ cycloalkyl group refers to a cyclic alkyl group having 3 to 8 carbon atoms, and also includes a group with a structure having bridged ring(s). As examples of C₃₋₈ cycloalkoxy groups, mention may be made of, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.

The C₃₋₈ cycloalkoxy group has a combined structure of a cyclic alkyl group having 3 to 8 carbon atoms and one oxy group (—O—). As examples of C₃₋₈ cycloalkoxy groups, mention may be made of, for example, a cyclopropyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, and the like.

The di(C₁₋₆ alkyl)amino group has a structure wherein each of two hydrogen atoms present on the amino group (—NH₂) is independently substituted with a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms. A di(C₁₋₄ alkyl)amino group is preferable. As examples of di(C₁₋₆ alkyl)amino groups, mention may be made of, for example, an N,N-dimethylamino group, an N,N-diethylamino group, and the like.

The C₂₋₆ alkoxycarbonyl group has a combined structure of a straight-chain or branched-chain alkoxy group having 1 to 5 carbon atoms and one carbonyl group (—CO—). A C₂₋₄ alkoxycarbonyl group is preferable. As examples of C₂₋₆ alkoxycarbonyl groups, mention may be made of, for example, a methoxycarbonyl group, an ethoxycarbonyl group, and the like.

The C₁₋₆ alkoxy C₁₋₆ alkoxy group has a combined structure of a C₁₋₆ alkoxy group and a C₁₋₆ alkoxy group. A C₁₋₄ alkoxy C₁₋₆ alkoxy group is preferable. As examples of C₁₋₆ alkoxy C₁₋₆ alkoxy groups, mention may be made of, for example, a methoxyethoxy group, an ethoxyethoxy group, and the like.

The di(C₁₋₆ alkyl)amino C₁₋₆ alkoxy group has a combined structure of a di(C₁₋₆ alkyl)amino group and a C₁₋₆ alkoxy group. A di(C₁₋₄ alkyl)amino C₁₋₄ alkoxy group is preferable. As examples of di(C₁₋₆ alkyl)amino C₁₋₆ alkoxy groups, mention may be made of, for example, an N,N-dimethylaminoethoxy group, an N,N-diethylaminoethoxy group, an N,N-diethylaminoethoxy group, and the like.

The C₂₋₁₀ alkenyl group refers to a straight-chain or branched-chain alkenyl group having at least one double bond and having 2 to 10 carbon atoms. As examples of C₂₋₁₀ alkenyl groups, mention may be made of, for example, an ethenyl group, a 1-propenyl group, a 2-propenyl group, a 2-methyl-1-propenyl group, a 1-butenyl group, a 3-butenyl group, cis-cis- and trans-cis-2,6-dimethyl-1,5-heptadienyl groups, a 2,6-dimethyl-5-heptenyl group, a 1,3-pentadienyl group, a 1,5-dimethyl-4-hexenyl group, and the like.

The C₂₋₆ alkynyl group refers to a straight-chain or branched-chain alkynyl group having at least one triple bond and having 2 to 6 carbon atoms. As examples of C₂₋₆ alkynyl groups, mention may be made of, for example, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 2-butynyl group, a 3-butynyl group, and the like.

The bicyclo[2.2.1]heptanyl group corresponds to a bicyclo-type saturated and bridged cyclic hydrocarbon group. As an example thereof, mention may be made of, for example, a bicyclo[2.2.1]hepta-2-yl group, or the like.

The “aryl” refers to a mono-valent group of an aromatic hydrocarbon such as phenyl, naphthyl, or the like. Therefore, in the present invention, the aryl group is a phenyl group, a naphthyl group, or the like, and preferably is a phenyl group. The substituted aryl group means a group wherein at least one hydrogen atom present on the ring thereof is substituted with a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group, a C₂₋₆ alkoxycarbonyl group, an aryl group, an aryloxy group, a phenethyl group, a cyano group, or a halogen atom. As the C₁₋₆ alkyl group, the C₁₋₆ alkoxy group, and the C₂₋₆ alkoxycarbonyl group for the substituents, a C₁₋₄ alkyl group, a C₁₋₄ alkoxy group, and a C₂₋₄ alkoxycarbonyl group are preferable, respectively. In particular, a methyl group, a methoxy group, and a methoxycarbonyl group are preferable, respectively. In addition, as the aryl group and the aryloxy group for the substituents, a phenyl group and a phenoxy group are preferable, respectively. The halogen atom may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, is preferably a fluorine atom, a chlorine atom, or a bromine atom, and is more preferably a fluorine atom or a chlorine atom.

As examples of the substituted aryl groups, mention may be made of a 3-methylphenyl group, a 4-methylphenyl group, a 2,3-dimethoxyphenyl group, a 3,4-dimethoxyphenyl group, a 4-methoxyphenyl group, a 3-methoxyphenyl group, a 2-methoxyphenyl group, a 3-phenoxyphenyl group, a biphenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 2,5-difluorophenyl group, a 2,4-dichlorophenyl group, a 4-fluorophenyl group, and the like.

The substituted or non-substituted arylamino group has a structure wherein one hydrogen atom of the amino group (—NH₂) is substituted with a substituted or non-substituted aryl group. As examples thereof, mention may be made of, for example, a phenylamino group, a 3-methylphenylamino group, and the like.

The C₁₋₆ alkyl (substituted or non-substituted aryl)amino group has a structure wherein one hydrogen atom of the amino group (—NH₂) is substituted with a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and the other hydrogen atom thereof is substituted with a substituted or non-substituted aryl group. As an example thereof, mention may be made of, for example, an N-ethyl-N-(3-methylphenyl)amino group, or the like.

The arylthio group has a combined structure of an aryl group and one thio group (—S—). As examples thereof, mention may be made of, for example, a phenylthio group, a naphthylthio group, and the like.

The aryloxy group has a combined structure of an aryl group and one oxy group (—O—). As examples thereof, mention may be made of, for example, a phenoxy group, a naphthoxy group, and the like.

The furyl group includes a 2-furyl group or a 3-furyl group.

The oxolanyl group has a structure of a saturated 5-membered ring having one oxygen atom (O) as a hetero atom, and includes a 2-oxolanyl group, or a 3-oxolanyl group.

The dioxolanyl group has a structure of a saturated 5-membered ring having two oxygen atoms (O) as hetero atoms (dioxolane), and preferably refers to a mono-valent group derived by eliminating a hydrogen atom from a 1,3-dioxolane ring. The substituted dioxolanyl group means a group wherein at least one hydrogen atom present on the group described above is substituted with a C₁₋₆ alkyl group and preferably a C₁₋₄ alkyl group. As an example thereof, a 2,2-dimethyl-1,3-dioxolan-4-yl group or the like may be given.

The oxanyl group has a structure of a saturated 6-membered ring having one oxygen atom (O) as a hetero atom. As examples thereof, mention may be made of, for example, a 2-oxanyl group, a 3-oxanyl group, a 4-oxanyl group, and the like.

The dioxanyl group has a structure of a saturated 6-membered ring having two oxygen atoms (O) as hetero atoms (dioxane). Preferably, it refers to a mono-valent group derived by eliminating a hydrogen atom from a 1,3-dioxane ring. The substituted dioxanyl group means a group wherein at least one hydrogen atom present on the group described above is substituted with a C₁₋₄ alkyl group. As an example thereof, a 5,5-dimethyl-1,3-dioxan-2-yl group or the like may be given.

The benzodioxanyl group refers to a mono-valent group derived by eliminating a hydrogen atom from a benzodioxane ring and preferably a 1,4-benzodioxane ring. As an example thereof, a 1,4-benzodioxan-2-yl group or the like may be given.

The phthalimidoyl group refers to a mono-valent group derived by eliminating a hydrogen atom present on the nitrogen atom of phthalimide.

The piperidino group refers to a mono-valent group derived by eliminating a hydrogen atom present on the nitrogen atom of piperidine.

The piperidyl group refers to a mono-valent group derived by eliminating a hydrogen atom present on the carbon atom of piperidine. The N—(C₁₋₆ alkyl)piperidyl group means a group wherein the nitrogen atom of a piperidyl group is substituted with a C₁₋₆ alkyl group. As examples thereof, mention may be made of, for example, a 3-(N-methylpiperidyl) group, a 4-(N-methylpiperidyl) group, and the like.

The pyridyl group includes a 2-pyridyl group, a 3-pyridyl group, or a 4-pyridyl group. In addition, the substituted pyridyl group means a group wherein at least one hydrogen atom present on the ring is substituted with a C₁₋₆ alkyl group, preferably a C₁₋₄ alkyl group, and more preferably a methyl group. As an example thereof, a 6-methyl-2-pyridyl group or the like may be given.

The pyridylthio group has a combined structure of a pyridyl group and one thio group (—S—). As examples thereof, mention may be made of, for example, a pyridin-2-ylthio group, a pyridin-3-ylthio group, a pyridin-4-ylthio group, and the like. A pyridin-2-ylthio group is preferable.

The pyrrolidinyl group refers to a mono-valent group derived by eliminating a hydrogen atom present on the nitrogen atom or the carbon atom of a pyrrolidine ring. As examples thereof, mention may be made of, for example, a 1-pyrrolidinyl group, a 2-pyrrolidinyl group, a 3-pyrrolidinyl group, and the like. A 1-pyrrolidinyl group is preferable.

The pyrrolyl group includes a 1-pyrrolyl group, a 2-pyrrolyl group, or a 3-pyrrolyl group. A 1-pyrrolyl group (N-pyrrolyl group) is preferable.

The thienyl group includes a 2-thienyl group, or a 3-thienyl group.

The thiazolyl group includes a 2-thiazolyl group, a 4-thiazolyl group, or a 5-thiazolyl group. In addition, the substituted thiazolyl group means a group wherein at least one hydrogen atom present on the ring is substituted with a C₁₋₆ alkyl group and preferably a C₁₋₄ alkyl group. As an example thereof, a 4-methyl-5-thiazolyl group or the like may be given.

The morpholino group refers to a mono-valent group derived by eliminating a hydrogen atom present on the nitrogen atom of morpholine.

The 2,6-purindion-7-yl group refers to a mono-valent group derived from 2,6-purindione wherein one oxygen atom (═O) is bonded to the carbon atom at the 2-position of the purine ring and one oxygen atom (═O) is bonded to the carbon atom at the 6-position of the purine ring, and refers to a group derived by eliminating a hydrogen atom present on the nitrogen atom at the 7-position. The substituted 2,6-purindion-7-yl means a group wherein at least one of the hydrogen atoms bonded to the nitrogen atom of the group is substituted with a C₁₋₆ alkyl group, preferably a C₁₋₄ alkyl group, and more preferably a methyl group. As an example thereof, a 1,3-dimethyl-2,6-purindion-7-yl group or the like may be given.

The “straight-chain C₂₋₁₀ alkylene group which may be substituted with a C₁₋₆ alkyl group or a trifluoromethyl group” defined in “A” means a straight-chain alkylene group having 2 to 10 carbon atoms, which may be substituted with one or more groups, and preferably one or two groups selected from straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms and trifluoromethyl groups. Among these, a straight-chain C₂₋₆ alkylene group which may be substituted with one or two methyl groups defined in “B” is preferable. As examples thereof, mention may be made of an ethylene group, a 1-methylethylene group, a propylene group, a 2,2-dimethylpropylene group, a butylene group, a 1-methylbutylene group, a hexylene group, a 1-trifluoromethylpropylene group, a heptylene group, a 4-methylpentylene group, a 3-methylbutylene group, a 1-methylpropylene group, a 3-methylpentylene group, a 1,1-dimethylethylene group, and the like. A 2,2-dimethylpropylene group, a hexylene group, and the like are preferable.

In addition, the pharmaceutically acceptable salt refers to a salt with an alkali metal, an alkali earth metal, ammonium, an alkylammonium, or the like, as well as, a salt with a mineral acid or an organic acid. As examples thereof, mention may be made of, for example, a sodium salt, a potassium salt, a calcium salt, an ammonium salt, an aluminum salt, a triethylammonium salt, an acetate, a propionate, a butyrate, a formate, a trifluoroacetate, a maleate, a tartarate, a citrate, a stearate, a succinate, an ethylsuccinate, a lactobionate, a gluconate, a glucoheptonate, a benzoate, a methanesulfonate, an ethanesulfonate, a 2-hydroxyethanesulfonate, a benzenesulfonate, a para-toluenesulfonate, a laurylsulfate, a malate, an aspartate, a glutamate, an adipate, a salt with a cysteine, a salt with an N-acetylcysteine, a hydrochloride, a hydrobromide, a phosphates, a sulfate, a hydroiodide, a nicotinate, an oxalate, a picrate, a thiocyanate, an undecanate, a salt with a polymeric acrylic acid, a salt with a carboxyvinyl polymer, and the like.

The compounds of the present invention can be synthesized according to, for example, the methods described below.

First, a compound represented by the formula (a) described below:

[wherein Y represents a halogen atom of any one of F, Cl, Br and I] and a compound represented by the formula (b) described below:

R¹XH  (b)

[wherein R¹ and X have the same meanings as described above] are reacted in the presence of an appropriate base to produce a compound represented by the formula (c) described below:

Subsequently, according to a common method for reducing an aromatic nitro group to an aromatic amino group, the compound represented by the above formula (c) is derived to a compound represented by the formula (d) described below:

Subsequently, the compound represented by the above formula (d) is reacted with dimethylformamide dimethylacetal in the presence or absence of an appropriate solvent for 2 to 72 hours at a temperature in the range of room temperature to 150° C., and preferably in the range of 70 to 100° C. to obtain an intermediate. Subsequently, by treating the intermediate, after isolation or in the state as produced, with hydroxylamine or a salt thereof such as a hydrochloride in a solvent such as methanol, the compound of the present invention can be synthesized.

Alternatively, the compound represented by the above formula (d) is reacted with an orthoformate such as trimethyl orthoformate, triethyl orthoformate, or the like in the presence of a catalytic amount of an organic acid such as acetic acid, a mineral acid such as hydrochloric acid, or a salt of a mineral acid and an amine such as pyridine hydrochloride, for 2 to 72 hours at a temperature in the range of room temperature to 150° C., and preferably in the range of 70 to 100° C. to obtain an intermediate. Subsequently, by treating the intermediate, after isolation or in the state as produced, with hydroxylamine in a solvent such as methanol, the compound of the present invention can be synthesized. As described above, the compounds of the present invention can be synthesized from the compounds represented by the above formula (d) using a common method for converting an amino group present on an aromatic ring into an N-hydroxyformamidine group.

The compounds and the pharmaceutically acceptable salts thereof according to the present invention can be administered orally or parenterally, in the form of tablets, capsules, granules, powders, troches, ointments, creams, emulsions, suspensions, suppositories, injectable solutions, or the like, each of which may be produced according to the conventional formulation methods (for example, methods defined in the 12^(th) revision of Japanese Pharmacopeia). These preparation forms may be selected depending on the conditions and ages of the patients, as well as the purpose of the treatment. Upon manufacturing preparations in various formulations, conventional fillers (for example, crystalline cellulose, starch, lactose, mannitol, or the like), binders (for example, hydroxypropylcellulose, polyvinylpyrrolidone, or the like), lubricants (for example, magnesium stearate, talc, or the like), disintegrants (for example, carboxymethylcellulose calcium, or the like), and the like, may be employed.

The dose of the compounds and the pharmaceutically acceptable salts thereof according to the present invention is preferably in the range of 1 to 2000 mg per day in the case of an adult human subject to be treated. They may be administered in a single dose or divided into several doses per day. The doses may appropriately vary depending on the age, weight, and conditions of each individual patient, and the like.

Best Modes for Carrying out the Invention

In the following, the present invention is illustrated in detail with reference to the following examples.

EXAMPLE 1

Synthesis of N-[2-(2-butyn-1-oxy)pyridin-5-yl]-N′-hydroxyformamidine (Compound 65)

Sodium hydride (60% in oil) (0.91 g, 22.7 mmol) was washed with dry hexane, and dimethylformamide (15 ml) and 2-butyn-1-ol (1.59 g, 22.7 mmol) were added thereto. The mixture was stirred for 1 hour at room temperature. The reaction mixture was cooled to 0° C., and a solution of 2-chloro-5-nitropyridine (3 g, 18.9 mmol) in dimethylformamide (20 ml) was added dropwise thereto. The mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over MgSO₄, and was subsequently concentrated under reduced pressure. Subsequently, iron powders (10.55 g, 189 mmol), isopropanol (10 ml), and a 1N aqueous solution of ammonium chloride (11.3 ml, 11.3 mmol) were added thereto. The mixture was stirred for 1 hour at 85° C. Ethyl acetate (100 ml) was added to the reaction mixture, and insoluble materials were removed therefrom by filtration with a celite. The filtrate was concentrated under reduced pressure, and subsequently a saturated aqueous solution of sodium hydrogencarbonate (20 ml) was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over MgSO₄, and was subsequently concentrated under reduced pressure. Subsequently, ethyl orthoformate (6.27 ml) was added thereto, and the mixture was stirred for 16 hours at 100° C. The reaction mixture was concentrated under reduced pressure. Subsequently, a 1N methanol solution of hydroxylamine (22.78 ml) was added thereto, and the mixture was stirred for one hour at room temperature. The reaction mixture was concentrated under reduced pressure to yield a crude product. The crude product was purified by NH type silica gel column chromatography (eluent, hexane:ethyl acetate=1:1), and was subsequently recrystallized from ethyl acetate/hexane to yield the target compound (Compound 65 in Table 1 described below) as of a colorless powder (0.654 g).

Melting point: 155.5 to 157.0° C.

EXAMPLE 2

Synthesis of N-[2-(3-dimethylamino-2,2-dimethylpropyl-1-oxy)pyridin-5-yl]-N′-hydroxyformamidine (Compound 123)

A mixture of 3-dimethylamino-2,2-dimethyl-1-propanol (82.8 g, 630 mml) and 2-chloro-5-nitropyridine (20 g, 126 mmol) was stirred for 6 hours at 100° C. Water was added to the reaction mixture, and the resulting precipitated crystals were obtained by filtration. The precipitate was dried, and methanol (330 ml) and palladium carbon (1.4 g) were added thereto. The mixture was stirred for 2 hours at room temperature. Subsequently, insoluble materials were removed therefrom by filtration with celite. The filtrate was concentrated under reduced pressure. Subsequently, methanol (250 ml) and dimethylformamide dimethylacetal (15.9 g, 133 mmol) were added thereto, and the mixture was stirred under reflux for 3 hours. The reaction mixture was cooled to room temperature. Subsequently, hydroxylamine hydrochloride (9.24 g, 133 mmol) was added thereto, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and subsequently a saturated aqueous solution of sodium hydrogencarbonate (10 ml) was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over MgSO₄, and was subsequently concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to yield the target compound (Compound 123 in Table 1 described below) as of a colorless powder (19.04 g).

Melting point: 74.0 to 76.5° C.

EXAMPLE 3 Synthesis of N-[2-(pyridin-2-ylmethoxy)pyridin-5-yl]-N′-hydroxyformamidine (Compound 6)

A mixture of 5-amino-2-(pyridin-2-ylmethoxy)pyridine (1.10 g) and ethyl orthoformate (1.782 g) was stirred for 8 hours at 100° C. Subsequently, excess ethyl orthoformate was removed. The residue in methanol (20 ml) was added a 1M methanol solution of hydroxylamine (8.2 ml). The mixture was stirred for 1 hour at room temperature. After removal of the solvent, chloroform was added to the obtained residue. The mixture was washed successively with water and saturated brine, and was subsequently dried over anhydrous sodium sulfate, followed by removal of the solvent. The obtained residue was recrystallized from chloroform to yield the target compound (Compound 6 in Table 1 described below) as of a colorless powder (0.374 g).

Melting point: 153.5 to 155.5° C.

EXAMPLE 4 Synthesis of N-[2-(benzylthio)pyridin-5-yl]-N′-hydroxyformamidine (Compound 104)

A mixture of 5-amino-2-(benzylthio)pyridine (1.11 g) and ethyl orthoformate (1.78 g) was stirred for 8 hours at 100° C. Subsequently, excess ethyl orthoformate was removed. The residue in methanol (20 ml) was added a 1 M methanol solution of hydroxylamine (8.2 ml). The mixture was stirred for 1 hour at room temperature. After removal of the solvent, chloroform was added to the obtained residue. The mixture was washed successively with water and saturated brine, and was subsequently dried over anhydrous sodium sulfate, followed by removal of the solvent. The obtained residue was recrystallized from chloroform to yield the target compound (Compound 104 in Table 1 described below) as of a colorless powder (0.45 g).

Melting point: 133.0 to 135.0° C.

EXAMPLES 5 to 134

In the following, the compounds shown in Table 1 described below were synthesized by carrying out similar reaction procedures to those of Examples 1 to 4 employing the corresponding starting materials.

TABLE 1 M + H M + H M − H M − H Inhibition IC50 Comp. No. Chemical Structure m.p. (ESI) (APCI) (ESI) (APCI) Rf Value TLC* Eluent (1 M) (nM) Comp. 1

133.5-135.5 264 262 0.11 SiO2 AcOEt 61.0 738.4 Comp. 2

130.5-132.5 250 248 0.07 SiO2 AcOEt 97.0 3095 Comp. 3

233 0.11 SiO2 AcOEt 102.0 49.6 Comp. 4

158.5-160.0 266 264 0.09 SiO2 AcOEt 99.0 339.2 Comp. 5

128.5-130.0 14.9 Comp. 6

153.5-155.5 244 0.1 SiO2 AcOEt 65.0 514.4 Comp. 7

104.5-106.0 41.9 781.4 Comp. 8

116.5-117.0 71.0 603.3 Comp. 9

163.5-164.0 82.9 9.1 Comp. 10

127.0-128.0 106.3 167.4 Comp. 11

156.5-157.0 249 247 0.17 SiO2 AcOEt 89.0 2.7 Comp. 12

90.0-91.5 255 253 0.14 SiO2 AcOEt 99.0 87.2 Comp. 13

97.0-97.5 267 265 0.16 SiO2 AcOEt 101.0 24.0 Comp. 14

125.0-126.0 271 269 0.16 SiO2 AcOEt 104.0 1.5 Comp. 15

159.0-160.0 249 0.15 SiO2 AcOEt 100.0 9.3 Comp. 16

252 250 0.14 SiO2 AcOEt 60.0 Comp. 17

159.0-160.0 278 276 0.1 SiO2 AcOEt 100.0 2.1 Comp. 18

221 0.17 SiO2 AcOEt 86.0 Comp. 19

239 237 0.17 SiO2 AcOEt 104.0 Comp. 20

205 203 0.17 SiO2 AcOEt 31.0 Comp. 21

207 205 0.15 SiO2 AcOEt 73.0 Comp. 22

125.2-126.0 263 261 0.17 SiO2 AcOEt 108.0 2.1 Comp. 23

192.0-192.5 244 242 0.09 SiO2 AcOEt 104.0 3.9 Comp. 24

272 270 0.17 SiO2 AcOEt Comp. 25

134.0-135.0 290 288 0.13 SiO2 AcOEt 71.0 9.6 Comp. 26

136.0-138.0 221 219 0.17 SiO2 AcOEt 99.0 27.2 Comp. 27

279 277 0.16 SiO2 AcOEt 71.0 Comp. 28

104.0-105.0 241 239 0.15 SiO2 AcOEt 105.0 9.9 Comp. 29

291 289 0.19 SiO2 AcOEt 101.0 Comp. 30

237 235 0.19 SiO2 AcOEt 102.0 Comp. 31

326 324 0.1 SiO2 AcOEt 40.0 Comp. 32

244 242 0.08 SiO2 AcOEt Comp. 33

122.0-123.0 272 270 0.1 SiO2 AcOEt 93.0 2.1 Comp. 34

107.0-108.0 295 293 0.17 SiO2 AcOEt 89.0 7.6 Comp. 35

261 259 0.18 SiO2 AcOEt 98.0 Comp. 36

145.0-146.0 287 285 0.18 SiO2 AcOEt 104.0 2.7 Comp. 37

181.5-183.5 272 270 0.08 SiO2 AcOEt 96.0 3.4 Comp. 38

169.5-170.0 249 247 0.16 SiO2 AcOEt 95.0 8.5 Comp. 39

223 221 0.19 SiO2 AcOEt 62.0 Comp. 40

233 231 0.15 SiO2 AcOEt 86.0 Comp. 41

258 256 0.14 SiO2 AcOEt 83.0 Comp. 42

238 236 0.24 SiO2 AcOEt 105.8 Comp. 43

252 250 0.24 SiO2 AcOEt 89.5 Comp. 44

266 264 0.25 SiO2 AcOEt 100.7 Comp. 45

143.0-144.5 208 206 0.21 SiO2 AcOEt 80.3 10.7 Comp. 46

151.0-152.0 220 0.20 SiO2 AcOEt 89.9 9.8 Comp. 47

82.0-84.0 222 220 0.23 SiO2 AcOEt 99.2 45.4 Comp. 48

238 236 0.23 SiO2 AcOEt 102.8 Comp. 49

238 236 0.23 SiO2 AcOEt 107.1 Comp. 50

300 298 0.23 SiO2 AcOEt 108.2 Comp. 51

288 0.25 SiO2 AcOEt 111.0 Comp. 52

288 0.24 SiO2 AcOEt 108.7 Comp. 53

123.0-125.0 224 222 0.23 SiO2 AcOEt 108.5 6.8 Comp. 54

120.0-122.0 222 220 0.22 SiO2 AcOEt 111.7 5.9 Comp. 55

119.0-120.0 208 206 0.22 SiO2 AcOEt 87.3 Comp. 56

124.5-125.5 220 218 0.21 SiO2 AcOEt 102.1 14.7 Comp. 57

264 262 0.22 SiO2 AcOEt 114.2 Comp. 58

234 232 0.2 SiO2 AcOEt 106.6 Comp. 59

 99.0-100.0 240 238 0.20 SiO2 AcOEt 109.6 4.4 Comp. 60

272 270 0.21 SiO2 AcOEt 109.9 Comp. 61

113.0-114.5 254 252 0.21 SiO2 AcOEt 99.8 13.1 Comp. 62

240 238 0.18 SiO2 AcOEt 112.8 Comp. 63

332 330 0.17 SiO2 AcOEt 102.3 Comp. 64

302 300 0.21 SiO2 AcOEt 100.7 Comp. 65

155.5-157.0 206 0.21 SiO2 AcOEt 86.9 68.2 Comp. 66

337 335 0.20 SiO2 AcOEt 105.3 Comp. 67

337 335 0.20 SiO2 AcOEt 108.6 Comp. 68

296 294 0.20 SiO2 AcOEt 102.6 Comp. 69

159.5-161.0 288 286 0.18 SiO2 AcOEt 102.8 6.5 Comp. 70

292 290 0.24 SiO2 AcOEt 108.1 Comp. 71

286 284 0.20 SiO2 AcOEt 99.0 Comp. 72

146.5-147.5 274 272 0.18 SiO2 AcOEt 92.9 59.0 Comp. 73

158.5-159.5 280 278 0.23 SiO2 AcOEt 105.0 6.4 Comp. 74

313 311 0.20 SiO2 AcOEt 69.3 Comp. 75

348 346 0.21 SiO2 AcOEt 88.5 Comp. 76

336 334 0.20 SiO2 AcOEt 100.2 Comp. 77

164.5-165.5 274 272 0.20 SiO2 AcOEt 100.3 3.3 Comp. 78

126.0-127.0 274 272 0.21 SiO2 AcOEt 100.2 4.2 Comp. 79

258 256 0.21 SiO2 AcOEt 100.6 Comp. 80

166.5-167.5 262 260 0.21 SiO2 AcOEt 102.9 3.9 Comp. 81

166.5-167.0 269 0.19 SiO2 AcOEt 104.4 1.7 Comp. 82

128.5-129.0 304 0.18 SiO2 AcOEt 104.5 60.1 Comp. 83

302 0.17 SiO2 AcOEt 98.8 Comp. 84

320 318 0.19 SiO2 AcOEt 105.3 Comp. 85

315 313 0.22 SiO2 AcOEt 100.8 Comp. 86

226 224 0.20 SiO2 AcOEt 82.6 Comp. 87

186.5-187.0 240 238 0.19 SiO2 AcOEt 87.0 264.3 Comp. 88

360 358 0.16 SiO2 AcOEt 71.8 Comp. 89

302 300 0.20 SiO2 AcOEt Comp. 90

186.5-167.0 247 245 0.17 SiO2 AcOEt 105.7 4.3 Comp. 91

140.0-141.0 261 259 0.19 SiO2 AcOEt 103.0 6.4 Comp. 92

111.5-112.0 228 226 0.21 SiO2 AcOEt 87.6 71.9 Comp. 93

109.0-111.0 242 240 0.21 SiO2 AcOEt 97.4 6.6 Comp. 94

153.0-154.0 274 272 0.21 SiO2 AcOEt 100.3 3.2 Comp. 95

290 288 0.21 SiO2 AcOEt 96.5 Comp. 96

114.0-115.0 238 236 0.18 SiO2 AcOEt 92.3 139.7 Comp. 97

149.5-152.5 252 250 0.19 SiO2 AcOEt 85.5 58.1 Comp. 98

137.5-138.5 264 262 0.20 SiO2 AcOEt 100.7 4.3 Comp. 99

138.0-140.0 264 262 0.21 SiO2 AcOEt 95.4 1.9 Comp. 100

294 292 292 0.30 SiO2 (NH) AcOEt 79.5 Comp. 101

252 252 250 250 0.30 SiO2 (NH) AcOEt 91.8 Comp. 102

141.0-142.0 212 212 210 210 0.32 SiO2 (NH) AcOEt 74.5 18.2 Comp. 103

256 254 254 0.28 SiO2 (NH) AcOEt 79.9 Comp. 104

133.0-135.0 260 258 258 0.28 SiO2 (NH) AcoEt 103.6 Comp. 105

226 226 224 224 0.32 SiO2 (NH) AcoEt 100.5 Comp. 106

240 240 238 238 0.35 SiO2 (NH) AcOEt 77.5 Comp. 107

115.0-115.5 214 214 212 212 0.10 SiO2 (NH) AcOEt 83.1 294.3 Comp. 108

242 240 240 0.25 SiO2 (NH) AcOEt 89.7 Comp. 109

153.5-154.5 238 238 236 236 0.30 SiO2 (NH) AcOEt 82.1 11.5 Comp. 110

140.5-141.5 250 250 248 248 0.30 SiO2 (NH) AcOEt 85.7 12.1 Comp. 111

125.5-127.5 226 226 224 224 0.35 SiO2 (NH) AcOEt 76.8 33.8 Comp. 112

240 240 238 238 0.35 SiO2 (NH) AcOEt 101.5 Comp. 113

254 254 252 252 0.38 SiO2 (NH) AcOEt 81.3 Comp. 114

268 266 266 0.38 SiO2 (NH) AcOEt 85.1 Comp. 115

296 294 294 0.38 SiO2 (NH) AcOEt 89.0 Comp. 116

256 256 254 0.30 SiO2 (NH) AcOEt 93.1 Comp. 117

174.5-175.0 226 224 224 0.30 SiO2 (NH) AcOEt 69.3 435.4 Comp. 118

270 268 268 0.32 SiO2 (NH) AcOEt 100.7 Comp. 119

274 274 272 272 0.32 SiO2 (NH) AcOEt 116.1 Comp. 120

105.0-105.5 228 228 226 226 0.13 SiO2 (NH) AcOEt 102.0 116.7 Comp. 121

143.5-144.5 192 0.20 SiO2 (NH) AcOEt 99.8 400.4 Comp. 122

295 99.6 623.7 Comp. 123

74.0-76.5 97.5 0.6 Comp. 124

122.0-124.0 92.6 141.6 Comp. 125

184 182 0.28 SiO2 (NH) AcOEt Comp. 126

153.5-154.5 Comp. 127

124.5-125.5 329.6 Comp. 128

131.0-133.0 279 277 0.14 SiO2 (NH) AcOEt 311.6 Comp. 129

109.0-111.0 335 333 0.34 SiO2 (NH) AcOEt Comp. 130

122 (dec.) 295 293 0.32 SiO2 (NH) AcOEt Comp. 131

105.0-106.0 225 223 0.11 SiO2 (NH) AcOEt Comp. 132

108.0-112.0 239 237 0.11 SiO2 (NH) AcOEt 566.2 Comp. 133

110.0-111.5 281 279 0.06 SiO2 (NH) Hex:AcOEt = 1:1 53.6 Comp. 134

91.0-93.0 307 305 0.29 SiO2 (NH) AcOEt *SiO2: Merck pre-coated plates Silica gel 60 F254, SiO2(NH): TLC plate NH Fuji Silysia Chemical LTD.

Experimental Example

[Inhibitory Effect of 20-HETE Synthase Derived from Rat Kidney Microsome]

Regarding the compounds listed in the Table described above, their inhibitory activities on production of 20-HETE were examined.

This examination was carried out based on the method described in J. Pharmacol. Exp. Ther., Vol. 268, p. 474 (1994).

The subject compound in an amount of 1 μM was added to a 50 mM of 3-morpholinopropanesulfonic acid buffer (MOPS) (pH 7.4), containing 5 mM of magnesium chloride, and 1 mM of ethylenediaminetetraacetic acid (EDTA) disodium salt.

Subsequently, the rat kidney microsome fraction prepared from the kidney of a spontaneously hypertensive rat (male, 6 weeks of age) as an enzyme, [5,6,8,9,11,12,14,15] tritium-arachidonic acid (supplied by Amasham) as a substrate, and NADPH (supplied by Sigma) as a coenzyme were added, and were reacted for 1.5 hours at 37° C.

After the reaction was quenched by adding formic acid (supplied by Wako Pure Chemical Industries Ltd.) to the reaction solution, acetonitrile (final concentration of 50%) was added thereto, and the mixture was allowed to stand for 1.5 hours at room temperature. The amount of 20-HETE production was measured by using a high performance liquid chromatography having a detector for radioactive substances (supplied by Gilson), equipped with an ODS column (Biocyl C18, supplied by Bio-rad).

Setting an amount of 20-HETE production to 100% when no subject compound was added, the inhibition rate (%) was calculated from the amount of 20-HETE production when a subject compound was added. The results thereof are also shown in the Table described above.

In addition, setting an amount of 20-HETE production to 100% when no subject compound was added, the concentration of the subject compound at which the production of the 20-HETE was inhibited to 50% when the subject compound is added (IC₅₀ value) was also calculated. The results thereof are also shown in the Table described above.

INDUSTRIAL APPLICABILITY

The compounds and the pharmaceutically acceptable salts thereof according to the present invention exhibit inhibitory activity on production of 20-HETE, and therefore, they are useful as therapeutic agents for diseases in human subjects and animals, which 20-HETE participates in, such as various kidney diseases, cerebrovascular diseases, or various circulatory diseases. 

What is claimed is:
 1. A hydroxyformamidine compound represented by the formula:

wherein R¹ is a group represented by the formula: R²—(CH₂)_(m)— (wherein R² is a C₃₋₈ cycloalkyl group, a C₂₋₆ alkoxycarbonyl group, a C₂₋₁₀ alkenyl group, a C₂₋₆ alkynyl group, a substituted or non-substituted aryl group, a furyl group, an oxolanyl group, a substituted or non-substituted dioxolanyl group, an oxanyl group, a substituted or non-substituted dioxanyl group, a benzodioxanyl group, a piperidyl group, an N—(C₁₋₆ alkyl)piperidyl group, a substituted or non-substituted pyridyl group, a thienyl group, a substituted or non-substituted thiazolyl group, or a bicyclo[2.2.1]heptanyl group, and m is an integer of 1 to 8), a group represented by the formula: R³—A— (wherein R³ is a hydrogen atom, a C₁₋₆ alkoxy group, a C₃₋₈ cycloalkoxy group, a di(C₁₋₆ alkyl)amino group, a substituted or non-substituted arylamino group, a C₁₋₆ alkyl (substituted or non-substituted aryl)amino group, a C₁₋₆ alkylthio group, a C₁₋₆ alkoxy C₁₋₆ alkoxy group, a di(C₁₋₆alkyl)amino C₁₋₆ alkoxy group, a hydroxy group, an acetoxy group, an arylthio group, an aryloxy group, a phthalimidoyl group, a piperidino group, a pyridylthio group, a pyrrolidinyl group, a pyrrolyl group, a morpholino group, or a substituted or non-substituted 2,6-purindion-7-yl group, and A is a straight-chain C₂₋₁₀ alkylene group which may be substituted with a C₁₋₆ alkyl group or a trifluoromethyl group), or a C₃₋₈ cycloalkyl group, and X is an oxygen atom or a sulfur atom, or a pharmaceutically acceptable salt thereof.
 2. The hydroxyformamidine compound or the pharmaceutically acceptable salt thereof, according to claim 1, wherein X is an oxygen atom.
 3. The hydroxyformamidine compound or the pharmaceutically acceptable salt thereof, according to claim 1, wherein X is an oxygen atom, and R¹ is a group represented by the formula: R⁴—B— (wherein R⁴ is a di(C₁₋₆ alkyl)amino group, a di(C₁₋₆ alkyl)amino C₁₋₆ alkoxy group, a piperidino group, a pyrrolidinyl group, or a morpholino group, and B is a straight-chain C₂₋₆ alkylene group which may be substituted with one or two methyl groups).
 4. A pharmaceutical composition comprising the hydroxyformamidine compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 as an active ingredient and a pharmaceutically acceptable carrier.
 5. An inhibitor for production of 20-hydroxyeicosatetraenoic acid, comprising the hydroxyformamidine compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 as an active ingredient.
 6. A therapeutic method for treatment of kidney diseases, cerebrovascular diseases, or circulatory diseases, comprising administering to a patient an effective amount of the hydroxyformamidine compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to
 3. 7. A method for inhibiting production of 20-hydroxyeicosatetraenoic acid, comprising administering to a patient in need thereof an effective amount of the hydroxyformamidine compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to
 3. 